Alteredγ-secretase activity in mild cognitive impairment and Alzheimer’s disease

Alteredγ-secretase activity in mild cognitive impairment and Alzheimer's disease

Nobuto Kakuda, Yasuo Ihara

Department of Neuropathology, Faculty of Life and Medical Sciences, and Center for Neurologic Diseases, Doshisha University

We investigated why the cerebrospinal fluid (CSF) concentrations of Aβ42 are lower in patients affected by mild cognitive impairment (MCI) and Alzheimer's disease (AD). Because Aβ38/42 and Aβ40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain γ-secretase activity, and were quantified by ELISA in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, Aβ42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, Aβ38 and 40, respectively. The ratios Aβ40/43 vs Aβ38/42 in CSF (each representing cleavage efficiency of Aβ43 or Aβ42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that γ-secretase activity in MCI/AD patients is enhanced at the conversion of Aβ43 and 42 to Aβ40 and 38, respectively. Consequently, we measured the in vivo activity of raft-associated γ-secretase isolated from control and MCI/AD brains and found the same, significant alterations in the γ-secretase activity in MCI/AD brains.

Address correspondence to Mr. Nobuto Kakuda, Department of Neuropathology, Faculty of Life and Medical Sciences, and Center for Neurologic Diseases, Doshisha University (4-1-1 Kizugawadai, Kizugawa, Kyoto 619-0225, Japan)